| First Author | Sase S | Year | 2020 |
| Journal | Elife | Volume | 9 |
| PubMed ID | 32463361 | Mgi Jnum | J:291062 |
| Mgi Id | MGI:6442504 | Doi | 10.7554/eLife.52986 |
| Citation | Sase S, et al. (2020) TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model. Elife 9:e52986 |
| abstractText | Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4a(D249N/+)) and the homozygous (Tubb4a(D249N/D249N)) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4a(D249N/D249N) mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4a(D249N/D249N) mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4a(D249N/D249N) mice. Thus Tubb4a(D249N/D249N) mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits. |
